Estra-1, 3, 5-(10)-trienes substituted at the 17alpha-position with a propadienyl or substituted propadienyl radical



United States Patent 0 "ice 3,392,165 ESTRA-1,3,5(10)-TRIENES SUBSTITUTED AT THE 17ct-POSITION WITH A PROPADIENYL 0R SUB- STITUTED PROPADIENYL RADICAL John A. Edwards, Los Altos, Calif., and Lawrence H. Knox, deceased, late of Mexico City, Mexico, by Anne A. Knox, Mexico City, Mexico, assignors to Syntax Corporation, Panama, Panama, a corporation of Panama No Drawing. Continuation-impart of application Ser. No. 514,136, Dec. 15, 1965. This application Mar. 30, 1966, Ser. No. 539,259

18 Claims. (Cl. 260-23955) This application is a continuation-in-part of United States application Ser. No. 514,136, filed Dec. 15, 1965.

This invention relates to novel cyclopentanophenanthrene derivatives having a 17a-diethylenically unsaturated side chain.

More particularly, the present invention relates to novel compounds of the formula:

R4 3 OR I O C C wherein R represents hydrogen, lower alkyl, cycloalkyl, a carboxylic acyl group of less than 12 carbon atoms, tetrahydropyran-Z-yl, or tetrahydrofuran-Z-yl; R represents hydrogen or a lower alkyl containing from 1 to 3 carbon atoms such as methyl, ethyl or propyl; R represents hydrogen, a carboxylic acyl group of less than 12 carbon atoms, tetrahydroypran-Z-yl, or tetrahydrofuran- 2-yl; and each of R R and R is hydrogen or methyl.

The carboxylic acyl groups of the compounds of the present invention contain less than 12 carbon atoms and may be of a straight, branched, cyclic or cyclic-aliphatic chain structure. This structure may be saturated, unsaturated, or aromatic and optionally substituted by functional groups such as hydroxy, alkoxy containing up to 5 carbon atoms, acyloxy containing up to 12 carbon atoms, nitro, amino, halogeno, and the like. Typical esters thus include acetate, propionate, enanthate, benzoate, trimethylacetate, t-butylacetate, phenoxyacetate, cyclopentyl propionate, aminoacetate, ,B-chloropropionate, adamantoate, and the like.

The lower alkyl groups represented by R in the above formula may be of straight or branched structure. Typical alkyl groups include methyl, ethyl, isopropyl, butyl, and the like, containing up to about 7 carbon atoms. The cycloalkyl groups represented by R in the above formula include, e.g., cyclopentyl, cyclohexyl, and the like, containing from 3 to about 7 carbon atoms.

The novel 17 u-diene steroids of the present invention possess estrogenic activity and are useful in the treatment of the various conditions in which such agents are indicated, such as estrogen difiiciencies, menopause, and the like. These compounds may also be used in veterinary medicine in the same manner as known estrogens and in the control and regulation of fertility. In addition, these agents demonstrate antiandrogenic activity. They may be administered in the usual pharmaceutical forms at dosages appropriate for the condition being'treated.

The compounds of the present invention may be pre- 3,392,165 Patented July 9, 1968 pared according to a process which may be illustrated as follows:

wherein R R R R R and R are as previously defined and X and Y are each bromo, chloro or fiuoro. This ring opening dehalogenation is preferably performed with those compounds wherein X and Y are chloro or bromo.

In practicing the above illustrated transformation, one method is to treat the 17a-dihalocycl0propyl compound with magnesium in a reaction medium such as diethyl ether, tetrahydrofuran, dioxane, or the like. The reaction may be conducted at a temperature of from room temperature to the reflux temperature for a period time of the order of two to twenty-four hours or more, preferably at reflux temperature for about two hours.

A second method for the preparation of the compounds of the present invention is to treat the 17a-dihalocyclopropyl steroids of Formula I with from about 3 to about 10 molar equivalents of an alkylsulfinyl carbanion such as sodium methylsulfinylcarbanion in dimethyl sulfoxide or other inert solvent medium such as the ethers, e.g. diethyl ether, tetrahydrofuran, dioxane, and the like at room temperature or above for a period of time of the order of about three to twenty-four hours or more.

A third method for accomplishing the transformation illustrated above is to treat the dihalocyclopropyl steroid I with a molar excess, preferably about 3 to 10 molar equivalents, of an alkali alkoxide, e.g. potassium tertiary bntoxide, in an inert solvent medium such as dimethyl sulfoxide, diethyl ether, dioxane, tetrahydrofuran, and the like, at room temperature or above for a period of time of the order of two to twenty-four hours or more.

The novel compounds of the present invention may also be prepared by treatment of the 17a-dihalocyclopropyl steroids (-1) with an alkyl lithium reagent such as butyl lithium in an inert solvent medium such as a hydrocarbon, ether, chlorinated hydrocarbon, and mixtures thereof, e.g. hexane and tetrahydrofuran. The alkyl lithium reagent should be present in a molar excess, for example, about 2 to 10 molar equivalents. The reaction may be conducted at room temperature or above and a time of the order of about 3 to 24 hours or more is usually required.

The 17a-dihalocyclopropyl starting compounds characterized by Formula I above are prepared according to a process which may be illustrated as follows:

wherein R R R R R R and X and Y are as defined above.

In the practice of the above illustrated process, an estra- 1,3,5()-triene having a vinyl or methyl substituted vinyl group in the 17a-position (H1) is treated with a dihalocarbene, as is generated for example from alkali metal salts of trihaloacetic acid, e.g., sodium trichloroacetate, sodium chlorodifiuoroacetate, sodium tribromoacetate, and sodium dichlorofluoroacetate, to yield the corresponding 17a-dihalocyclopropyl derivatives of Formula I. The reaction is conducted under anhydrous conditions in an inert organic solvent such as diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, or the like. Other reagents known to generate dihalocar- 'benes, such as trimethyl (trifluoromethyl) tin, phenyl(trichloromethyDmercury, phenyl (bromodich1oromethyl)- mercury, and the like, with sodium iodide, may also be used in a similar fashion. The l7a-dibromocyclopropyl compounds may also be prepared through the action of bromoform and potassium t-butoxide on a 17a-alkenyl derivative of Formula HI.

The l7a-alkenyl compounds of Formula LII may be readily prepared from the corresponding 17-keto compounds through conventional methods, e.g. treatment with alkenyl magnesium halides. Alternatively, the l7a-alkenyl compounds may be obtained from the corresponding 17ccalkynyl compounds through controlled hydrogenation in accordance with conventional procedures.

The 17a-alkenyl-17e-hydroxy compounds may be converted to the corresponding l7fi-acyloxy, l7p-tetrahydropyran-Z-yloxy, or 17,8-tetrahydrofuran-2-yloxy derivatives via conventional methods prior to preparing the 170:- cyclopropyl steroids of Formula I or may be esterified or etherified thereafter.

The substituent in the 3-position of the estratriene nucleus of the novel compounds of the present invention may be a hydroxy group or an etherified, e.g. methoxy, tetrahydropyran-Z-yloxy, tetrahydrofuran-Z-yloxy, cyclopentyloxy, and the like, or an esterified, e.g. acetoxy, benzoyloxy, and the like, derivative thereof. These derivatives may be formed prior to the preparation of the novel 17a-dienes of Formula II of the present invention or may be formed thereafter via conventional methods. Thus treatment with an appropriate carboxylic acid anhydride, such as acetic anhydride, in pyridine with a 3,17fi-dihydroxy compound yields the 3-acyloxy-l7p-hydroxy derivative selectively. Use of an acid anhydride in the presence of the corresponding acid and an acid catalyst such as p-toluenesulfonic acid yields the 3,17,8-diacyloxy derivative. This diester may then be selectively saponified as through the use of methanolic potassium bicarbonate to yield the corresponding 3-hydroxy-17fi-acyloxy derivative. Similarly, etherification may be performed via conventional procedures. Thus, treatment with dihydropyran in the presence of an acid catalyst such as p-toluenesulfonic acid, p-toluenesulfonyl chloride, dinitrobenzene sulfonic acid or the like, yields the corresponding tetrahydropyran-Z-yloxy derivative. Formation of the monotetrahydropyranyl ether may be accomplished by selective protection of other hydroxy groups as through ester formation, in the manner described above, with alkaline hydrolysis of such ester groups after formation of the ether, if desired. Formation of 3-methoxy derivatives may likewise be realized through the use of dimethylsulfate and potassium hydroxide in the conventional manner.

The following detailed examples are presented to illustrate the preparation of the novel compounds of the present invention, not as a limitation thereof.

Example 1 A solution of 5 g. of 3-hydroxyestra-1,3,5(10)-trien- 17-one in 250 ml. of thiophene-free benzene is treated with 10 equivalents of isopropenylmagnesium bromide in anhydrous ether. The mixture is heated at reflux under anhydrous conditions for 24 hours, cooled, and cautiously treated with ethyl acetate and these extracts are in turn washed with water, dried over sodium sulfate and evaporated to dryness to yield l7a-isopropenylestra-1,3,5-(l0)- triene-3,l7 8-diol which may be recrystallized from methylene chloridezhexane.

In a similiar manner, 3-hydroxy-18-methylestra-l,3,5 (10)-trien-17-one, 3-hydroxy-18 ethylestra l,3,5(10)- trien-l7-one, and 3-hydroxy-l8-n-propylestra-l,3,5(10)- trien-l7-one are subjected to the foregoing procedure to yield the corresponding Nix-isopropenyl-l7 8-hydroxy compounds.

By the use of 3-methyl-2-butenylrnagnesium bromide in the foregoing procedure, there is obtained 17m-(3'-methyl- 2-butenyl-estra- 1,3,5 (10)-triene-3, 17,8-diol; 17a-( 3 -methyl-2-butenyl)-l8-methylestra 1,3,5(10) triene 3,175- diol, 17a-(3-methyl-2'-butenyl)-18-ethylestra 1,3,5(10)- triene-3,17 3-diol, and 174x-(3-methyl-2'-butenyl) 18 npropylestra- 1,3,5 10) -triene-3, l7fl-diol, respectively.

By the use of l-methyl-l-propenylmagnesium bromide, l-propenylmagnesium bromide and vinylmagnesium bromide in the foregoing procedure, the corresponding 17a- (1'-methyl- '-propenyl) and 17a-(1'-propenyl) and 170:- vinyl derivatives are obtained.

The Grignard reagents employed in the foregoing procedure are prepared via conventional procedures from magnesium and an appropriate olefinic halide. Thus, the Grignard reagents may be prepared in the following manner.

To a mixture of 8.0 g. of magnesium shavings and ml. of dry ether cooled in an ice-bath, there is added, with stirring, 24 g. of 2-bromo3-methyl-2-butene in 40 ml. of dry ether in a dropwise manner. After addition is complete, the mixture is refluxed for one hour to furnish 3- 'methyl-2-butenylmagnesium bromide.

In a similar fashion, by use of the appropriate olefinic bromide, i.e. vinyl bromide, 2-bromo-2-butene, 2-bromol-propene, and l-bromo-l-propene, in the foregoing procedure, the corresponding Grignard reagent is obtained, i.e. vinylmagnesium bromide, l-methyl-l-propenylmagnesium bromide, isopropenylmagnesium bromide, and 1- propenylmagnesium bromide, respectively.

A mixture of 1 g. of 17a-isopropenylestra-1,3,5(l0)- triene-3,17p-diol, 1 g. of p-toluenesulfonic acid monohydrate, 50 ml. of acetic acid and 25 ml. of acetic anhydride is allowed to stand at room temperature for 24 hours, and then poured into water and stirred. This mixture is then extracted with methylene chloride and these extracts are dried and evaporated to yield 3,17B-diacetoxy-17a-isopropenylestra-1,3,5()-triene, which is recrystallized from acetonezether.

In a similar manner, the other 3,17/3-diol compounds prepared above may be converted to the corresponding 3,17B-diacetoxy derivatives. Through the use of other acids and anhydrides in the above procedure, the corresponding diacylates are similarly prepared.

One gram of 3,17/3-diacetoxy-l7a-isopropenylestra-1,3,5 (10)-triene is allowed to stand at room temperature for hours with 1 g. of potassium bicarbonate in 10 ml. of Water and 90 ml. of methanol. At the end of this time, the methanol is evaporated under reduced pressure and the residue is extracted With ethyl acetate and water. Evaporation of the ethyl acetate from these extracts yields 175- acetoxy-l7a-isopropenylestra-1,3,5 (10)-trien-3-ol which is collected by filtration and recrystallized from acetone: hexane.

To a refluxing solution of 5 g. of l7fl-acetoxy-l7uisopropenylestra-l,3,5(10)-trien-3-ol in 500 m1. of ethanol are added over a 30 minute period ml. of dimethyl sulfate and 80 g. of potassium hydroxide in 50 ml. of Water, 5 ml. portions of each be alternately added. The mixture is then refluxed for 45 minutes, cooled and poured into ice water. The solid which forms upon neutralization with hydrochloric acid is collected, washed with water and dried to yield 3-methoxy-l7/3-acetoxy-17a-isopropeuylestra-1,3,5(10)-triene which is recrystallized from chloroformzmethanol.

In a similar fashion, the above prepared 3,17B-diacetoxy derivatives may be subjected to the foregoing procedure to obtain the corresponding 3-methoxy-l718-acetoxy derivatives.

The requisite 17a-alkenyl starting materials may also be prepared by subjecting a 17a-alkynyl compound to hydrogenation in the following manner.

A solution of 1 g. of 3-methoxy-17a-ethynyl-18-methylestra-l,3,5(10)-trien-l7fi-ol in 40 ml. of pyridiene is hydrogenated at C. atmospheric pressure in the presence of 0.4 g. of prehydrogenated 2% palladium-on-calcium carbonate. When 1.1 molar equivalents of hydrogen are absorbed, the reaction is stopped. The catalyst is removed by filtration through Celite diatomaceous earth and Washed with ethyl acetate and the combined filtrate and washings are evaporated to dryness under reduced pressure. The residue is dissolved in ethyl acetate and this solution then washed with dilute hydrochloric acid and water to neutrality, dried and evaporated to dryness to yield 3-methoxy-l7a-vinyl-18-methylestra-1,3,5 (10)-trien-17/8-ol which is further purified through recrystallization from acetone.

In a similar manner, by use of the foregoing procedure other 17a-alkynyl compounds may be converted to the corresponding 17a-alkenyl derivatives, for example, 17mmethylethynyl to 17a-methy1vinyl (1'-propenyl).

Example 2 To a refluxing solution of 1 g. of 3-rnethoxy-17a-vinyl- 17,8-acetoxyestra-1,3,5(10)-triene in 10 ml. of diethylene glycol dimethyl ether is added over a two hour period in a dropwise fashion with stirring, a solution of molar equivalents of sodium trichloroacetate in ml. of diethylene glycol dimethyl ether. After refluxing for an additional hour, the mixture is filtered. The filtrate is evaporated to dryness and the residue is chromatographed on alumina, eluting with methylene chloride, to yield 3-methoxy-l7ot-(2,2-dichlorocyclopropyl) 17/8 acetoxyestral,3,5(l0)-triene.

In alike fashion,

3-methoxy- 17a-V1HY1- 17B-acetoxy-1 8-methylestra 1,3,5 l0) -triene,

17a-vinyl-17,8-acetoxyestra-1,3,5 10 -trien-3-ol,

3-methoxy-l7a-isopropenyl-l75-acetoxyestra-1,3,5 10) triene,

3 -methoxy-l7ul'-methyl- 1 -pr0penyl) -l 8-ethyl- 1719- acetoxyestra-1,3,5 l0) triene,

6 17a- 1'-propenyl)-estra-1,3,5(10)-triene-3,l7;8-diol, 17B-acetoxy-17u-(1-propenyl)-estra-1,3,5(10)-trien-3-ol, 17,8-acetoxy-17a-vinyl-18-methylestra-l,3,5 10) -trien- 3-ol, 17,8-acetoxy-17a-viny1-18-n-propylestra-1,3,5( 10) trien-3-ol, and 17w 3 '-methyl-2'-butenyl) -estra-l,3,5 10 -triene-3, 17B- diol are subjected to the foregoing procedure to yield 3-methoxy-17a(2',2'-dichlorocyclopropyl)-17fi-acetoxyl8-methylestra-l,3,5(10)-triene,

l7oc-( 2,2-dichloro cyclopropyl -17 fi-acetoxyestra- 1,3,5 10) -trien-3-ol,

3-methoxy-17u 2,2'-dichloro-1'-methylcyclopropyl 17 B-acetoxyestra-l ,3,5 l0) -triene,

3-methoxy 1711- 2',2'-dichloro-l ',3-dimethylcyclopropyl) l Scthyl- 17 B-acetoxyestra- 1,3,5( 10 -triene,

17,8-acetoxy- 17c:- 2',2'-dichloro-3-methylcyclopropyl estra- 1,3,5 1 0 -trien-3-ol,

17,8-acetoxy-17a- (2',2-dichlorocyclopropyl) -18-methylestra-l,3,5(10)-trien-3-ol,

l7B-acetoxy-171x-(2,2'-dichlorocyclopropyl) -1 8-npropylestra- 1, 3,5 10 -trien-3-ol, and

17 oz (2',2'-dichloro- 1,3',3 '-trimethylcyclopropyl) -estra- 1,3,5 l0 -triene-3, l7 8-diol, respectively.

By the use of sodium tribromoacetate in the above procedure, the corresponding dibromo derivatives are obtained, e.g.

3-methoxy-17a- (2',2-dibromo-cyclopropyl) -17 3-acetoxyestra-l,3,5(10)-triene,

3-methoxy-17u- (2,2'-dibromocyclopropyl -17,B-acetoxyl8-methylestra-l ,3,5 (10)-triene,

17a-(2',2'-dibromocyclopropyl) -17B-acetoxyestra- 1,3,5 lO)-trien-3-ol,

17 a- (2,2-dibromo-3'-methylcyclopropyl) 17 B-acetoxycstra-l,3,5(10)-trien-3-ol, etc.

By the use of sodium chlorodifluoroacetate in the foregoing procedure, the corresponding difluoro derivatives are obtained, e.g. 3-methoxy-l7m-(2,2'-difluorocyclopropyl)-l7fl-acetoxyestra-l,3,5(10)-triene.

The corresponding 17,8-hydroxy derivatives may be alternatively used in the foregoing procedure, the products thus obtained being similarly unesterified in the 17B-position.

Example 3 A solution of 0.17 g. of potassium hydroxide in 0.2 ml. of water and 2.5 ml. of methanol is added over 30 minutes to a refluxing solution of l g. of 3-methoxy-l7;8 acetoxy-l7a-(2,2' dichlorocyclopropyl)-estra-l,3,5 10)- triene in 30 ml. of methanol under nitrogen. The solution is refluxed for 2 hours, cooled, neutralized with acetic acid and concentrated under reduced pressure. After the addition of water, the solid which forms is collected by filtration and dried to yield 3-methoxy-17u-(2,2'-dichlorocyclopropyl)-estra-l,3,5(10)-trien-17fi-ol which is recrystalized from acetonezhexane.

Similarly, using the above procedure, the other 17,8- acetoxy-17a-dihalocyclopropyl compounds are converted into the corresponding l7/3-hydroxy derivatives.

Example 4 Two milliliters of dihydropyran are added to a solution of l g. of 3-methoxy-17a-(2,2'-dichlorocyclopropyl)- estra-l,3,5(10)-trien-l7/i-ol in 15 ml. of benzene. About 1 ml. is removed by distillation to remove moisture and 0.4 g.- of p-toluenes-ulfonic acid is added to the cooled solution. This mixture is allowed to stand at room temperature for 4 days, and is then washed with aqueous sodium carbonate solution and water, dried and evaporated. The residue is chromatographed on neutral alumina, eluting with hexane, to yield 3-methoxy-l7a-(2',2'- dichlorocy-clopropyl) 17 5- (tetrahydropyran-2.-yloxy)- 7 estra-1,3,5(10)-triene which is recrystallized from pentane.

Use of this process with the other 17,8-hydroxy compounds described above will similarly yield the corre sponding 17 3-tetrahydropyran-2'-yloxy derivatives. Similarly, use of the foregoing procedure with 3,17,8-dio1 compounds, e.g. 17a-(2,2'-dibr0mo-3-methylcyclopropyl)- estra-1,3,5(10)-triene-3,l7[3-diol, 17a-(2',2'-dichlorocyclopropyl)-18-methylestra 1,3,5(10)-tiiene-3,l7f3-diol and doubling the amount of dihydropyran present in the reaction mixture furnishes the corresponding bistetrahydropyran-2-yl ethers, e.g. 17a-(2',2-dibromo-3'-methylcyclopropy1)-3,l7/8-bis(tetrahydropyran-2-yloxy) estra-l,3,5- (10)-triene and 171x-(2,2'-dichlorocyclopropyl)6,175- bis (tetrahydropyran-2-yloxy) -18-methylestra 1,3,5 10)- triene.

Example 5 A mixture of l g. of 17a-(2',2-dichlorocyclopropyl)- estra-1,3,5()-triene-3,l7;3-diol, 4 ml. of pyridine and 2 ml. of acetic anhydride is allowed to stand at room temperature for hours. The mixture is then poured into ice water and the solid which forms is collected by filtration, washed with water and dried to yield 3-acetoxy-17a- (2',2' dichlorocyclopropyl)-estra-l,3,5(10)-trien-17fi-ol which may be further purified through recrystallization from acetonezhexane.

In a similar manner, the other 3-hydr-oxy-l7u-(2',2- dihalocyclopropyl) compounds may be selectively converted to the corresponding 3-acetoxy derivatives, as for example 3-acetoxy-17u-(2,2'-dibromocycl-opropy1)-estra- 1,3,5( 10)-trien-17fi-ol. Through the use of other anhydrides in the foregoing procedure, the corresponding 3- acylates are similarly prepared.

Example 6 A mixture of 1 g. of l7a-(2',2-dichlorocyclopropyl)- estra-1,3,5(10)-triene-3,17fl-diol, 1 g. of p-toluenesulfonic acid monohydrate, 50 ml. of acetic acid and ml. of acetic anhydride is allowed to stand at room temperature for 24 hours, and then poured into water and stirred. This mixture is then extracted with methylene chloride and these extracts are dried and evaporated to yield 3,17fl-diacetoxy-17m-(2',2 chlorocyclopropyl) estral,3,5(10)-triene, which is recrystallized from acetone: ether.

In a similar manner, other 3,17 3-diol-17a-dihalocyclopropyl compounds may be converted to the corresponding 3,17B-diacetoxy derivatives, e.-g. 3,l7fi-diacetoxy-l7a-(2,- 2.-dibromocyclopropyl) -estra- 1,3,5 l 0) -triene.

One gram of 3,l7o-diacetoxy-17a-(2,2-dichlorocyclopropyl)-estra-l,3,5(10)-triene is allowed to stand at room temperature for 15 hours with 1 g. of potassium bicarbonate in 10 ml. of water and 90 ml. of methanol. At the end of this time, the methanol is evaporated under reduced pressure and the residue is extracted with ethyl acetate and water. Evaporation of the ethyl acetate from these extracts yields 17B-acetoxy-17a-(2',2-dichlorocyclopropyl)-estra-l,3,5(10)-triene-3-ol which is collected by filtration and recrystallized from acetonezhexane.

Two milliliters of dihydropyran are added to a solution of 1 g. of l7fi-acetoxy-17m-(2',2'-dichlorocycl0propyl)- estra-1,3,5(10)-trien-3-ol in 15 ml. of benzene. About 1 ml. is removed by distillation to remove moisture and 0.4 g. of p-toluenesulfonic acid is added to the cooled solution. This mixture is allowed to stand at room temperature for 4 days, and is then washed with aqueous sodium carbonate solution and water, dried and evaporated. The residue is chromatographed on neutral alumina, eluting with hexane, to yield 3-(tetrahydropyran- 2-yl'oxy) -17;3-acetoxy-l7c-(2,2' dichlorocyclopropyl) estra-1,3,5(10)-triene which is recrystallized from pentane.

' A solution of 0.17 g. of potassium hydroxide in 0.2 ml. of water and 2.5 ml. of methanol is added over minutes to a refluxing solution of 1 g. of 3-(tetrahydropy- 8 ran-2-yloxy)17;3-acetoxy-l7a-(2',2' dichlorocyclopropyl)-estra-'1,3,5( 10)-triene in 30 ml. of methanol under nitrogen. The solution is refluxed for 2 hours, cooled, neutralized with acetic acid and concentrated under reduced pressure. After the addition of water, the solid which forms is collected by fillration and dried to yield 3-(tetrahydropyran-2-yloxy) 17a (2',2-dichlorocyclopropyl)-estra-1,3,5('10)-triene-17,B-ol which is recrystallized from acetonezhexanc.

Example 7 Two milliliters of dihydropyran are added to a solution of 1 g. of 3-acetoxy-17a (2',2-dichlorocyclopropyl)- estra-1,3,5(10)-trien-17/i-ol in 15 ml. of benzene. About 1 ml. is removed by distillation to remove moisture and 0.4 g. of p-toluenesulfonic acid is added to the cooled solution. This mixture is allowed to stand at room temperature for 4 days, and is then Washed with aqueous sodium carbonate solution and water, dried and evaporated. The residue is chromatographed on neutral alumina, elu-ting with hexane, to yield 3-acetoxy-l7a- (2',2-dichlorocyclopropyl) 17 8 (tetrahydropyran-2'- yloxy)-estra-1,3,5(10)-triene which is recrystallized from pentane.

One gram of the thus-prepared compound is allowed to stand at room temperature for 15 hours with 1 g. of potassium bicarbonate in 10 ml. of water and 90 ml. of methanol. At the end of this time, the methanol is evaporated under reduced pressure and the residue is extracted with ethyl acetate and water. Evaporation of the ethyl' acetate from these extracts yields 17u-(2,=2'-dichlorocyclopropyl) 17B (tetrahydropyran-2'-yloxy)-estra-1,6,5 (10)-trien-3-ol, which is collected by filtration and recrystallized from acetone:hexane.

Example 8 lowed by 10% hydrochloric acid. The ether layer is separated, dried and evaporated to give 3-methoxy-l-7upropadieuyl-l7,B-acetoxyestra-1,3,5(10)-triene.

Example 9 A mixture of 1 g. of 3-hydroxy-l7ot-(2',2'-dichlorocy clopropyl) 17/3 (tetrahydropyran-2'-yloxy)-estra-1,3,5 (10)-triene, 4 molar equivalents of sodium methylsul-finylcarbanion, and 40 ml. of dimethylsulfoxide under nitrogen is allowed to stand at room temperature for 24 hours. Thereafter, the reaction mixture is poured into water and extracted with methylene chloride. The organic extract is washed with water, dried, and evaporated to yield 3-hydroxy-'17a-propadieny1 1713 (tetrahydropyran-2'- yloxy)-estra-l,3,5(10)-triene.

A mixture of the thus-prepared 3-hydroxy-17a-propadienyl 17o (tetrahydropyran-2'-yloxy)-estra-1,3,5 l0)-triene and 25 ml. of formic acid is stirred at room temperature for about one hour. The mixture is poured into water and the solid which forms is collected by filtration, washed well with water, and dried to yield 3, l7fi-diol-17a-propadieny1estra-1,3,5 10) -triene.

Example 10 Five milliliters of dihydropyran are added to a solution of 1 g. of 17a-propadienylestra-1,3,5(l0)-triene-3,l7;8- diol in 20 ml. of benzene. About 1 ml. is removed by distillation to remove moisture and 0.6 g. of p-toluencsulfonic acid is added to the cooled solution. This mixture is allowed to stand at room temperature for 4 days, and is then washed with aqueous sodium carbonate solution and water, dried and evaporated. The residue is chromatographed on neutral alumina, eluting with hexane, to yield 9 3,17--bis(tetrahydropyran-2'-yloxy) 17a propadienylestIa-1,3,5(10)-triene which is recrystallized from pentane.

Example 11 To a solution of 1 g. of 3-methoxy-17a-(2,2'-dichlorocyclopropyl) 175 (tetrahydropyran-2-yloxy)-estra-1,3, 5 )-triene in 40 ml. of anhydrous diethyl ether under nitrogen is added dropwise over a ten minute period with stirring 3 molar equivalents of butyl lithium in anhydrous diethyl ether while maintaining the reaction temperature at -35 C. The reaction mixture is allowed to stand for one hour at a temperature of -35 C. Thereafter, the reaction mixture is permitted to rise to room temperature and is then poured into water. The resulting mixture is extracted with methylene chloridezethyl acetate and the organic extract Washed with water, dried and evaporated to dryness to yield 3-meth0xy-17a-propadieny1 l75-(tetrahydropyran-2-yloxy) -estra-.1,3,5=( 10) -triene.

Example 12 A mixture of 1 g. of 3-hydroxy-1 7u=(2,2-dibromocy clopropyl)-175 (tetrahydropyran 2' yloxy)-estra-1,3, 5 (10)-triene, 4 molar equivalents of potassium-t-butoxide, and 35 ml. of dimethyl sulfoxide under nitrogen is allowed to stand at room temperature for 24 hours. Then, the reaction mixture is poured into water, extracted with methylene chloride and the extracts washed with water, dried and evaporated to dryness afiording 3-hydroxy-17apropadieny1-175-(tetrahydropyran 2' yloxy)-estra-'1,'3, 5( 10) -triene.

Example 13 A mixture of 1 g. of 17a-(2',2-dichlorocyclopropyl)- 175-acetoxyestra-1,3,5(10)-triene-3-ol, 5 molar equivalents of cyclopentyl bromide, and 0.5 g. of potassium carbonate in 30 ml. of acetone is refluxed for 24 hours. The reaction mixture is cooled to room temperature and then poured into water. The resulting mixture is extracted with methylene chloride and the organic extracts washed, dried and concentrated to dryness to yield 3-cyclopentoxy- 17a-(2',2'-dichlorocyclopropyl)-175-acetoxyestra 1,3,5- (10)-triene which may be further purified through recrystallization fi'om methylene chloride:hexane.

Use of the foregoing procedure with other 3-hydroxy compounds will similarly yield the corresponding 3-cyclopentoxy derivatives.

Likewise, through the use of n-butyl bromide in the foregoing procedure in lieu of cyclopentyl bromide, the corresponding 3-n-butyl ether, i.e., 3-n-butoxy-17a-(2,2' dichlorocyclopropyl) l75-acetoxyestra-1,3,5(10) triene is obtained.

By subjecting 3-cyclopentoxy-17u-(2',2'-dichlorocyclopropyl)-175-acetoxyestra-1,3,5(10)-triene to the process of Example 8, there is obtained 3-cyclopentoxy-17upropadienyl-175-acetoxyestra-1,3,5(10)-triene.

Example 14 The method of Example 8 is repeated using as the starting materials 3-methoxy-17a-(2',2-dichlorocyclopropyl)-l75-acetoxy 18 methylestra-1,3,5(10) triene, 3,175-diacetoxy-17a (2',2' dibromocyclopropyl)-estra- 1,3,5 (10)-triene, 3- (tetrahydropyran-2'-yloxy) -17a- (2,2'- dichlorocyclopropyl)-175-acetoxyestra 1,3,5 10) -triene and 3 (tetrahydropyran-2'-yloxy)-17u-(2',2-dibromocyclopropyl) 18 methyl 175 acetoxyestra 1,3,5- (10)-triene thus producing 3-methoxy17a-propadienyl- 175-acetoxy-IS-methylestra 1,3,5(10) triene, 3,175-diacetoxy-17a-propadienylestra-1,3,5 (10)-triene, 3-hydroxy- 17cc-propadienyl-l75-acetoxyestra-1,3,5(10)-triene and 3- hydroxy-17a-propadienyl-18 ethyl 175 acetoxyestra- 1,3,5 10)-triene, respectively.

Example 15 The method of Example 8 is repeated using as the starting materials 3-n-butoxy-17u-(2',2'-dichlorocyclopropyl)--acetoxy-estra-1,3,5(10)-triene, 3 methoxy- 17a-(2,2'-dichloro-1'-methyl-cyclopropyl)-175 acetoxyestra-1,3,5(10)-triene, 3-methoxy 17a (2,2-dichloro- 1',3-dimethylcyclopropyl) 175 (tetrahydropyran 2- yloxy)-estra-1,3,5(10)-triene, and 3,175-diacetoxy-17a- (2',2'-dichloro 3' methylcyclopropyl) 18 ethylestra- 1,3,5 (10)-triene, thus obtaining 3-n-butoxy-17a-propadienyl-175-acetoxyestra-1,3,5 (10)-triene, 3-methoxy-17a- (1-methylpropadienyl) 175 acetoxyestra 1,3,5 (10)- triene, 3-methoxy-17a-(1',3 -dimethylpropadienyl) -175- (tetrahydropyran-2'-yloxy) estra 1,3,5 (10)-triene, and 3,175-diacetoxy-17r-(3-methylpropadienyl) 18 ethylestra-1,3,5(10)-triene, respectively.

Example 16 A mixture of 2 g. of 17a-propadienyl-175-(tetrahydropyran-2-yloxy)-estra-1,3,5(10)-trien-3-ol in 8 ml. of pyridine and 4 ml. of benzoyl chloride is heated at steam bath temperatures for one hour. The mixture is then poured into ice water and the solid which forms is collected by filtration, washed with water and dried to yield 3-benzoyloxy-17a propadienyl 175 (tetrahydropyran- 2-yloxy)-estra-1,3,5(10)-triene which is further purified through recrystallization from methylene chloride:hexane.

Use of this process with the other 3-hydroxy compounds of the present invention will similarly yield the corresponding 3-benzoyloxy derivatives.

Example 18 A mixture of 1 g. of 17u-propadienyl-1S-methylestra- 1,3,5 (10)-triene-3,175-diol, 4 ml. of pyridine and 2 ml. of acetic anhydride is allowed to stand at room temperature for 15 hours. The mixture is then poured into ice water and the solid which forms is collected by filtration, washed with water and dried to yield 3-acetoxy- 17apropadienyl-18-methylestra-1,3,5 (10) trien 175-01 which may be further purified through recrystallization from acetonechexane.

In a similar manner, the other 3-hydroxy compounds of the present invention, e.g., 17a-propadienylestra-1,3,5- (10)triene-3,175-diol, may be converted into the corresponding 3-acetoxy derivatives, e.g., 3-acetoxy-17a-propadienylestra-1,3,5(10)-trien-175-ol. Through the use of other anhydrides, e.g., propionic anhydride and the like, in this process, the corresponding 3-acylates, e.g., 3-propionate, are similarly prepared.

Example 19 A mixture of 1 g. of 17a-propadienylestra-1,3,5(10)- triene-3,175-diol, 1 g. of p-toluenesulfonic acid monohydrate, 50 ml. of acetic acid and 25 ml. of acetic anhydride is allowed to stand at room temperature for 24 hours, and then poured into Water and stirred. This mixture is then extracted with methylene chloride and these extracts are dried and evaporated to yield 3,175-diacetoxy-17a-propadienylestra-1,3,5(10)-triene, which is recrystallized from acetone ether.

One gram of the above-prepared 3,175-diacetate is and 17,8-acetxy-3-hydroxy derivatives, respectively.

Example 20 Two grams of 3-acetoxy-17a-propadienylestra-1,3,5-(10) trien-17/8-ol in 50 ml. of dry diethylene glycol dimethyl ether is added over a 10 minute period to a slurry of 1.3 molar equivalents of sodium hydride in 50 ml. of dry diethylene glycol dimethyl ether. To this mixture is then added 1.1 molar equivalents of 2-chlorotetrahydrofuran in dropwise fashion over a period of about 10 minutes. The resulting mixture is allowed to stand at room temperature for about 24 hours and then warmed on a steam bath for about 1 hour. The mixture is diluted with water and then extracted with ether. The ether extracts are then washed, dried and evaporated to yield 3-acetoxy-17B-(tetrahydrofuran-2-yloxy) 17a-propadienylestra-1,3,5 10)-triene.

By repeating the above process and using other compounds of the present invention having a free hydroxy group in position 3 or 17, the corresponding tetrahydrofuranyl ether derivative, e. g. 3-(tetrahydrofuran-2-yloxy)- 17,8-acetoxy-17a-propadienylestra 1,3,5 (10) triene, 3- methoxy-l7,8-(tetrahydrofuran-2-yloxy) 17cc propadicnylstra-1,3,5(10)-triene, etc. is obtained,

Similarly, by repeating the process of this example with the exception of using twice the amount of reagents employed above, the 3,17,8-diol compounds of the present invention may be converted into the corresponding 3,176- bis-tetrahydrofuran-Z-yl ethers, e.g. 3,l'7{l-bis(tetrahydrofuran-2'-yloxy)17e-propadienyl 18 methylestra 1,3, ()-triene.

' Example 21 Two milliliters of dihydropyran are added to a solution of 1 g. of 3-hydroxy-17a-propadienyl-175-acetoxyestra-1,3,5(10)-triene in ml. of benzene. About 1 ml. is removed by distillation to remove moisture and 0.4 g. of p-toluenesulfonic acid is added to the cooled solution. This mixture is allowed to stand at room temperature for 4 days, and is then Washed with aqueous sodium carbonate solution and water, dried and evaporated. The residue is chromatographed on neutral alumina, eluting with hexane, to yield 3-(tetrahydropyran-Z-yloxy)-17a-propadienyl-l7/3-acetoxyestra-l,3,5(l0)-triene which is recystallized from pentane.

Example 22 A solution of 0.17 g. of potassium hydroxide in 0.2 ml. of water and 2.5 ml. of methanol is added over 30 minutes to a refluxing solution of 1 g. of 3-(tetrahydropyran-2'- yloxy)-17a-propadienyl-l7fi-acetoxyestra 1,3,5(10) triene in 30 ml. of methanol under nitrogen. The solution is refluxed for 2 hours, cooled, neutralized with acetic acid and concentrated under reduced pressure. After the addition of water, the solid which forms is collected by filtration and dried to yield 3-(tetrahydropyran-2-yloxy)- l7a-propadienylestra-1,3,5 (10)-trien-17;9-ol which is recrystallized from acetone:hexane.

Likewise, through the use of the process of this example, other 17 3-acyloxy compounds, e.g. 3-l'l16thOXY-l7ccpropadienyl-l7,8-acetoxy-IS-methylestra 1,3,5 (10) triene, of the present invention may be converted into the corresponding 17f3-hydroxy derivatives.

Example 23 A mixture of l g. of 3-n-butoxy-l7a-propadienyl-i75- 12 (tetrahydropyran-Z yloxy)-estra-l,3,5(l@)-triene, 40 ml. of methanol and 15 ml. of 5% oxalic acid is refluxed for about one hour. The reaction mixture is cooled and then poured into water. The resulting mixture is extracted with methylene chloride and the organic extracts washed with Water, dried, and concentrated to dryness to yield 3-hbutoxy-17x-propadicnylestra-1,3,5(1Q)trien-17B-ol.

By use of the forgoing procedure, the other tetrahydropyranyl and tetrahydroturanyl ethers of the present invetion may be converted to the corresponding ree hydroxyl derivatives.

Example 24 A mixture of 1 g. of 3-benzoyloxy-17m-propadienyl- 17,8-(tetrahydropyran-Z-yloxy)-estra-1,3,5 10)-triene, 40 ml. of dioxane, and 10 ml. of 1% sulfuric acid is allowed to stand at room temperature for 10 minutes. The mixture is then neutralized, concentrated under vacuum to a small volume and poured into water. The solid which forms is collected by filtration, washed well with water, and dried to yield 3-benzoyloxy-l7oa-propadienylestra- 1,3,5(10)-trien-17B-ol.

What is claimed is:

1. A compound of the formula wherein:

R is selected from the group consisting of hydrogen, lower alkyl, cycloallzyl, a carboxylic acyl group of less than 12 carbon atoms, tetrahydropyran-Z-yl, and tetrahydrofuran-Z-yl;

R is selected from the group consisting of hydrogen and lower alkyl containing from 1 to 3 carbon atoms;

R is selected from the group consisting of hydrogen, a carboxylic acyl group of less than 12 carbon atoms, tetrahydropyran-Z-yl, and tetrahydrofuran-2-yl; and

each of R R and R is selected from the group consisting of hydrogen and methyl.

2. A compound according to claim 1 wherein R R and R are each hydrogen.

3. A compound according to claim 1 wherein R R, R and R are each hydrogen and R is tctrahydropyran- 2-yl.

4. A compound according to claim 1 wherein R is methyl and R R and R are each hydrogen.

5. A compound according to claim 1 wherein R is methyl and R R R and R are each hydrogen.

6. A compound according to' claim 1 wherein R is methyl and R R R, R and R are each hydrogen.

7. A compound according to claim 1 wherein R is cyclopentyl and R R and R are each hydrogen.

8. A compound according to claim 1 wherein R is tetrahydropyran-Z-yl and R R and R are each hydrogen.

9. A compound according to claim 1 wherein R is tetrahydropyran-Z-yl and R R R and R are each hydrogen.

10. A compound according to claim 1 wherein R is tetrahydropyran-Z-yl, R is acetyl and R R and R are each hydrogen.

11. A' compound according to claim 1 wherein R is butyl and R R and R are each hydrogen.

benzoyl and R, R and R are each hydrogen. 7

13 14 13. A compound according to claim 1 wherein R R 13. A compound according to claim 1 wherein R R R and R are each hydrogen. R R R and R are each hydrogen.

14. A corn-pound according to claim 1 wherein R is methyl and R R and R are each hydrogen. Rgfergnces {lit 15. A compound according to claim 1 wherein R is 5 P methyl and R and R are each hydrogen. UNITLD QTATES PATENTS 16. A compound according to claim 1 wherein R is 3,107,257 10/1963 Counsel} 26O 397-5 methyl and R and R are each hydrogen. u

17. A compound according to claim 1 wherein R is LEWIS GOTTS Pmm'y Exammen methyl. 10 T. M. MESHBESHER, Assistant Examiner.

Notice of Adverse Decision in Interference In Interference N0. 97 ,277 involving Patent No. 3,392,165, J. A. Edwards and L. H. Knox, deceased, by A. A. Knox, ESTRA-1,3,5 (10)1R1ENES SUB- STITUTED AT THE 17 a-POSITION IVITII A PROPADIENYL OR SUBSTITUTED PROPADIENYL RADICAL, final judgment adverse to the patentees was rendered May 10, 1974, as to claim 15.

[Ofiicial Gazette of September 21,, 1974.] 

1. A COMPOUND OF THE FORMULA
 8. A COMPOUND ACCORDING TO CLAIM 1 WHEREIN R1 IS TETRAHYDROPYRAN-2-YL AND R4, R5 AND R6 ARE EACH HYDROGEN. 